Many new chemical entities are too potent, too toxic, or too water-insoluble, making them undesirable development candidates. Potency and toxicity are intrinsic to molecular design and are typically best remedied by altering or refining chemical structure. On the other hand, poor solubility typically leads to poor oral bioavailability, fed/fasted variations in bioavailability, cumbersome and inconvenient dosage forms, and may necessitate the use of harsh solubilizing agents that are associated with adverse side effects. Anew generation of nanoparticulate drug delivery systems specifically designed for resolving formulation issues associated with these poorly water-soluble compounds could be solving the problem (see, e.g., Liversidge G, Cundy K. “Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs”. Int. J. Pharm. 1995, 125:91-97).
Nanoparticles, in comparison to micronized drug particles, have significantly greater surface area. The increase in surface area enhances dissolution rate, thereby improving delivery efficiency for the most commonly-used routes of administration (Jinno J. et al. “Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs”, J. Cont. Rel. 2006, 206(111): 56-64).
A number of methods are available to produce drug nanoparticles, involving either top-down processes, based upon attrition, or bottom-up processes, based upon molecular deposition. Examples of the latter include spray freezing into liquid (SFL), rapid expansion from a liquefied-gas solution (RESS), and gas antisolvent recrystallization (GAS). RESS and GAS represent two approaches in development based upon supercritical fluid technology (Pathak P, Meziani M J, Sun Y-P., “Supercritical fluid technology for enhanced drug delivery”, Expert Opin. Drug Deliv. 2005(2):747-761). RESS is used for compounds that are soluble in supercritical fluids. The resulting solution is subjected to a rapid reduction in pressure and/or a rapid elevation in temperature, causing the solute to emerge from solution. Under optimal conditions, submicron particles can be generated. The GAS process is used for compounds that are not soluble in supercritical fluids. The compound is first dissolved in an organic solvent and then re-crystallized by admixing with the supercritical fluid. More recently, Microfluidics (Newtown, Mass.) has employed impinging-jet crystallization technology to produce crystalline nanoparticles (Panagiotou T, Fisher R J. “Form Nanoparticles via Controlled Crystallization”, Chemical Engineering Progress 2008:33-39).
The alternate path for generating drug nanoparticles entails top-down processes. Large drug crystals (typically >5 microns in diameter) are subjected either to high-pressure homogenization or high-energy wet milling in a fluid phase consisting essentially of water, yielding drug particles in the nanometer size range (Merisko-Liversidge E, Liversidge G G, Cooper E R. “Nanosizing: a formulation approach for poorly-water-soluble compounds”, Eur. J. Pharm. Sci. 2004, 18:113-20).
A key to the success of both processes is the inclusion of surface modifiers in the fluid phase. The surface modifiers prevent aggregation and/or Ostwald ripening of the nanoparticles during and after processing. Surface modifiers are chosen from the list of pharmaceutically-acceptable substances and typically possess surface active properties capable of wetting the large drug crystals and providing steric and/or ionic stabilization to the resulting nanometer-size drug particles. Some of the most commonly-used stabilizers include povidones, phospholipids, polysorbates, poloxamers, cellulosics, and anionic surfactants, e.g. SLS and DOSS.
Microfluidizer technology is based on the use of the microfluidizer, which is a jet stream homogenizer of two fluid streams collied frontally with high velocity (up to 100 m/sec) under pressures of up to 4000 bar. Turbulent flow and high shear forces cause particles collision, leading to particle diminution to the nanometer range. The high pressure applied and the high streaming velocity of the lipid can also lead to cavitation, additionally contributing to size diminution. To preserve the particles size, stabilization with phospholipids or other surfactants and stabilizers is required. A major disadvantage of this process is the required production time. In many cases, 50 to 100-time consuming passes are necessary for a sufficient particle size reduction (U.S. Pat. Nos. 6,018,080 and 5,091,187). The high-pressure homogenization/microfluidization approach has been investigated over the years (Muller R. H., “Nanosuspensions as particulate drug formulations in therapy: rationale for development and what we can expect in the future”, Adv. Drug Delivery Rev. 2001, 47:3-19; Rabinow B. E., “Nanosuspensions in drug delivery”, Nature Reviews: Drug Delivery 2004, 3:785-796; Pace S. et al., “Novel injectable formulations of insoluble drugs”, Pharm. Tech, 1999, 23:116-134; and Panagiotou T. et al., “Production of stable nanosuspensions using mircofluidics reaction technology”, Nanotech. 2007, 4:246-249). High-energy wet milling process is also known (Bottomley K, “NanoTechnology for Drug Delivery: a Validated Technology?”, Drug Delivery Report, 2006:20-21).
There are advantages and disadvantages to each approach. Published particle size data for homogenization processes indicate that this approach typically produces a dispersion with slightly broader particle size distribution relative to what has been achievable using the wet milling approach (Shah J, Wisniecki P, Wagner D, Shah P. “Case study: development of parenteral nanosuspensions: stability, manufacture and performance”. At 42nd Annual Technology Arden Conference: Best Practices for Parenteral Dosage Forms: Formulation, Process, Development, Package Selection and Manufacturing. AAPS Meetings and Expositions, West Point, N.Y. 2007.) Also, high-energy wet milling typically uses a proprietary milling media in which contact points between the media and the drug particles bring about particle size reduction. The media used in Elan's NanoCrystal technology approach, for example, comprises highly cross-linked polystyrene spheres that have been engineered to withstand high shear forces, thereby minimizing concerns about media wear during manufacturing (Merisko-Liversidge E, Liversidge G G, “Drug Nanoparticles: Formulating Poorly Water-Soluble Compounds”, Toxicology Pathology 2008, 36:43-48). The result is a population of drug nanoparticles characterized by high purity and a tight, reproducible particle-size distribution profile.
Formulating poorly water-soluble molecules using the various nano-sizing approaches adds tremendous value throughout the drug development cycle. NanoCrystal formulations can be prepared with as a little as 10 mg of active ingredient, and are often times used as clips to identify the optimal development candidate based on bioavailability and efficacy (U.S. Pat. No. 5,091,187). These formulations can be dosed via multiple routes of administration, and since the formulations are well-tolerated and provide maximal exposure for a poorly water-soluble compound, they are an invaluable tool for toxicokinetic studies and target product profile.
A major challenge in realizing the full commercial potential of nanosizing is the successful conversion of stable drug nanoparticles into acceptable dosage forms. Furthermore, while microfluidization process has been used in connection with injectable formulations, the use of that process is much less common in connection with oral formulations. Regardless of the success in development of nanosizing technologies, the existing drawbacks trigger a need for more sophisticated procedures to obtain oral nanosuspensions of poorly soluble drugs with improved bioavailability.